Shedding new light on vitamin D and fatty liver disease
Refers to article:
Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats , 22 December 2010
Toshiaki Nakano, Yu-Fan Cheng, Chia-Yun Lai, Li-Wen Hsu, Yen-Chen Chang, Jia-Yi Deng, Yu-Zhu Huang, Hiroyuki Honda, Kuang-Den Chen, Chih-Chi Wang, King-Wah Chiu, Bruno Jawan, Hock-Liew Eng, Shigeru Goto, Chao-Long Chen
Journal of Hepatology
August 2011 (Vol. 55, Issue 2, Pages 415-425)
Abstract | Full Text | Full-Text PDF (2767 KB) | Add-Ons
Fig. 1. Vitamin D-mediated effects on fatty liver disease. Anti-inflammatory, anti-fibrotic, and metabolic effects of vitamin D on parenchymal (hepatocytes) and non-parenchymal hepatic cells (hepatic stellate cells, Kupffer cells, and lymphocytes) are induced in fatty livers. Metabolic effects of vitamin D on the cholesterol 7α-hydroxylase (CYP7A1) and on forkhead transcription factor 1 (FOXO1), a central mediator in the insulin signalling pathway, are mediated via intestinal activation of fibroblast growth factor 15/19 and hepatic FGF receptor 4 (FGFR4) signalling. Furthermore, apolipoprotein (APOE) expression is induced. In white adipose tissue (WAT), adiponectin expression is activated by vitamin D treatment.
Understanding the complex interplay between vitamin D signals and lipid/glucose metabolism and differentiating specific metabolic effects from nonspecific anti-inflammatory properties in fatty liver disease may open new therapeutic interventions for the future in this constantly increasing threat to public health. The first confirmation of therapeutic potency of sunlight therapy and vitamin D in an animal model of fatty liver disease clearly builds the basis for subsequent human therapeutic trials in NAFLD.
Vitamin D substitution represents a simple, cheap and almost side effect-free candidate approach to reduce the burden of end-stage liver failure and liver cancer in this frequent disease entity for which medical interventions with proven longterm efficacy are still lacking.
Conflict of interest
The author declared that he does not have anything to disclose regarding conflict of interest with respect to this manuscript.
. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. CrossRef
. Holick MF. Vitamin D: Evolutionary, Physiological and Health Perspectives. Curr Drug Targets. 2011;12:4–18. CrossRef
. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116:2062–2072. MEDLINE | CrossRef
. Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005;26:662–687. CrossRef
. Dusso AS, Sato T, Arcidiacono MV, Alvarez-Hernandez D, Yang J, Gonzalez-Suarez I, et al. Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl. 2006;2:S8–S11.
. Bitetto D, Fabris C, Falleti E, Fornasiere E, Fumolo E, Fontanini E, et al. Vitamin D and the risk of acute allograft rejection following human liver transplantation. Liver Int. 2010;30:417–444.
. Fisher L, Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease. Clin Gastroenterol Hepatol. 2007;5:513–520. Abstract | Full Text | Full-Text PDF (159 KB) | CrossRef
. Tsuneoka K, Tameda Y, Takase K, Nakano T. Osteodystrophy in patients with chronic hepatitis and liver cirrhosis. J Gastroenterol. 1996;31:669–678. MEDLINE | CrossRef
. Masuda S, Okano T, Osawa K, Shinjo M, Suematsu T, Kobayashi T. Concentrations of vitamin D-binding protein and vitamin D metabolites in plasma of patients with liver cirrhosis. J Nutr Sci Vitaminol (Tokyo). 1989;35:225–234. MEDLINE
. Petta S, Camma C, Scazzone C, Tripodo C, Di Marco V, Bono A, et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51:1158–1167. CrossRef
. Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007;17:517–524. Abstract | Full Text | Full-Text PDF (131 KB) | CrossRef
. Manco M, Ciampalini P, Nobili V. Low levels of 25-hydroxyvitamin D(3) in children with biopsy-proven nonalcoholic fatty liver disease. Hepatology. 2010;51:2229. CrossRef
. Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta. 2006;371:1–12. MEDLINE | CrossRef
. Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35:126–131. MEDLINE | CrossRef
. Nakano T, Cheng YF, Lai CY, Hsu LW, Chang YC, Deng JY, et al. Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J Hepatol. 2011;55:415–425. Abstract | Full Text | Full-Text PDF (2766 KB)
. Zuñiga S, Firrincieli D, Lasnier E, Miquel JF, Housset C, Chignard N. Invalidation of the vitamin D nuclear receptor promotes liver steatosis. In: Annual meeting American association for the study of liver disease. Boston, MA: Hepatology; 2010, p. 1058A.
. Sandgren ME, Bronnegard M, DeLuca HF. Tissue distribution of the 1,25-dihydroxyvitamin D3 receptor in the male rat. Biochem Biophys Res Commun. 1991;181:611–616. CrossRef
. Segura C, Alonso M, Fraga C, Garcia-Caballero T, Dieguez C, Perez-Fernandez R. Vitamin D receptor ontogenesis in rat liver. Histochem Cell Biol. 1999;112:163–167. MEDLINE | CrossRef
. Gascon-Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology. 2003;37:1034–1042. MEDLINE | CrossRef
. Evans R. Nuclear receptors and liver disease – the Hyman Zimmerman state-of-the-art lecture. In: Annual meeting American association for the study of liver disease. Boston, MA; 2008,
. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2:217–225. MEDLINE | CrossRef
. Schmidt DR, Holmstrom SR, Fon Tacer K, Bookout AL, Kliewer SA, Mangelsdorf DJ. Regulation of bile acid synthesis by fat-soluble vitamins A and D. J Biol Chem. 2010;285:14486–14494. CrossRef
. Song KH, Li T, Owsley E, Strom S, Chiang JY. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology. 2009;49:297–305. CrossRef
. Li T, Owsley E, Matozel M, Hsu P, Novak CM, Chiang JY. Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice. Hepatology. 2010;52:678–690. CrossRef
. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the medical research council ely prospective study 1990–2000. Diabetes. 2008;57:2619–2625. CrossRef
. Hypponen E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British birth cohort. Diabetes. 2008;57:298–305. CrossRef
. Liu E, Meigs JB, Pittas AG, McKeown NM, Economos CD, Booth SL, et al. Plasma 25-hydroxyvitamin d is associated with markers of the insulin resistant phenotype in nondiabetic adults. J Nutr. 2009;139:329–334. CrossRef
. Gannage-Yared MH, Chedid R, Khalife S, Azzi E, Zoghbi F, Halaby G. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population. Eur J Endocrinol. 2009;160:965–971. CrossRef
. Stein EM, Strain G, Sinha N, Ortiz D, Pomp A, Dakin G, et al. Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study. Clin Endocrinol (Oxf). 2009;71:176–183. CrossRef
. Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298:G440–G445. CrossRef
. Nagpal J, Pande JN, Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabet Med. 2009;26:19–27. CrossRef
. von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – a randomised, placebo-controlled trial. Br J Nutr. 2010;103:549–555. CrossRef